PROJECT SUMMARY/ABSTRACT The Androgen Receptor (AR) may be the earliest known example of a lineage oncogene: a master regulator of cell survival and growth to which neoplastic cells derived from prostate epithelium are addicted. Recognizing this unique feature, concerted efforts have focused on developing therapeutics capable of suppressing AR signaling. Emerging strategies, mirroring successes in treatment for infectious diseases, will eventually deploy combinations of drugs that will likely extinguish AR signaling, an event that may cure a subset of prostate cancers. However, the plasticity of carcinomas, in part generated by highly unstable genomes, suggests that prostate cancers are likely to emerge from this therapeutic pressure with a phenotype/genotype that is entirely independent of AR signaling. This proposal is designed to anticipate that combinatorial AR pathway inhibition will contribute to cell plasticity and select for subpopulations of resistant tumor cells that are completely independent of AR signaling and do not exhibit neuroendocrine characteristics. We will test the hypothesis that AR Pathway-Independent Prostate Cancers (APIPC) activate, and are dependent upon, a limited set of specific survival and growth regulatory pathways that are regulated via de-repressed feedback loops and/or genetic/epigenetic alterations in specific oncogenic networks. Our Aims and strategies are as follows: Specific Aim 1: Determine the mechanisms by which fibroblast growth factor (FGF) signaling promotes the progression of AR-dependent PC to AR-null APIPC and assess outcomes of FGF-targeted therapeutics. Cell lines and PDX models of disease representing a spectrum of AR-dependent and AR-independent lines will be evaluated. Specific Aim 2: Determine the mechanisms contributing to FGF pathway activation in APIPC. We will utilize relevant in vivo model systems and biospecimens to determine genomic and epigenomic mechanism(s) that activate FGF signaling and determine how the FGF pathway promotes adverse prostate cancer phenotypes. Specific Aim 3: Identify and target mechanisms of resistance to FGF pathway inhibition and to other drivers of prostate cancer lineage plasticity. We will evaluate relevant model systems and human biospecimens for the heterogeneity and diversity of mechanisms contributing to tumor cell plasticity, and assess the effectiveness of therapeutics that intercept, reverse or inhibit emerging drivers. In order for effective therapeutics to be developed that can adequately address this new class of malignancy, the pathways utilized by APIPC must first be clearly defined; this project aims to elucidate those underlying mechanisms.